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. 2023 Nov;202(1):191-201.
doi: 10.1007/s10549-023-07046-3. Epub 2023 Aug 17.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes

Lauren Lenz  1 , Chris Neff  1 , Cara Solimeno  1 , Elizabeth S Cogan  1 , Vandana G Abramson  2 , Judy C Boughey  3 , Carla Falkson  4 , Matthew P Goetz  3 , James M Ford  5 , William J Gradishar  6 , Rachel C Jankowitz  7 , Virginia G Kaklamani  8 , P Kelly Marcom  9 , Andrea L Richardson  10 , Anna Maria Storniolo  11 , Nadine M Tung  12 , Shaveta Vinayak  13   14 , Darren R Hodgson  15 , Zhongwu Lai  16 , Simon Dearden  15 , Bryan T Hennessy  17 , Erica L Mayer  18   19 , Gordon B Mills  20 , Thomas P Slavin  1 , Alexander Gutin  1 , Roisin M Connolly  21 , Melinda L Telli  5 , Vered Stearns  10 , Jerry S Lanchbury  1 , Kirsten M Timms  22
Affiliations

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes

Lauren Lenz et al. Breast Cancer Res Treat. 2023 Nov.

Abstract

Purpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer.

Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes.

Results: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy.

Conclusions: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

Keywords: Breast cancer; DNA damage; Genomic instability; Homologous recombination deficiency; Tumor biomarker.

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Conflict of interest statement

Ms. Lenz, Mr. Neff, Ms. Solimeno, Dr. Cogan, Dr. Slavin, Dr. Gutin, Dr. Lanchbury and Dr. Timms were all employed by Myriad Genetics at the time of this study and received salary and stock options. Dr. Abramson has received consulting fees from AstraZeneca, Eisai, Daiichi Sankyo, Macrogenics, and Seagen. Dr. Boughey has received research funding from Lilly and participated in a Data Safety Monitoring Board with Cairns Surgical. Dr. Falkson has received honoraria from Exact Sciences, Curio Sciences, Agendia, and Biotheranostics for advisory boards; has received honoraria from OncLive/MJH Life Sciences for Speaker’s Bureau activity; and has received research funding to institution from Oncolytics Biotech, Quantumleap Health, and Eli Lilly. Dr. Goetz has received personal fees for CME activities from Research to Practice and Clinical Education Alliance; has received consulting fees to the Mayo Clinic from AstraZeneca, Biovica, Biotheranostics, Blueprint Medicines, Eagles Pharmaceuticals, Lilly, Novartis, Pfizer, and Sermonix; and has received grant funding to the Mayo Clinic from Lilly, Pfizer, and Sermonix. Dr. Ford has received research funding from Pfizer, Genentech, Merus, PUMA, and AstraZeneca. Dr. Kaklamani has received speaker fees from Pfizer, Gilead, Genentech, Genomic Health, Puma, Eisai, Novartis, Daiichi Sankyo, and Seagen; has received consultant fees from Puma, AstraZeneca, Athenex, and Gilead; and has received research funding from Eisai. Dr. Marcom is employed by Veracyte, Inc. Dr. Richardson is an inventor on an IP owned by Partners Healthcare and licensed to Myriad Genetics. Dr. Storniolo has received consulting fees from AstraZeneca. Dr. Tung has received research funding from AstraZeneca and has consulted for GSK. Dr. Hodgson, Dr. Lai, and Mr. Dearden were employed by AstraZeneca at the time of the study and received salary and restricted stock shares. Dr. Hennessy has received research funding from Bayer, AstraZeneca, and Daiichi Sankyo and has received royalties from Myriad Genetics. Dr. Mayer has received consulting fees from Lilly, Novartis, AstraZeneca, and Gilead. Dr. Mills is on the scientific advisory board for Amphista, Astex, AstraZeneca, BlueDot, Chrysalis Biotechnology, Ellipses Pharma, ImmunoMet, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Quereator, Roche, SignalChem Lifesciences, Tarveda, Turbine, and Zentalis Pharmaceuticals; has stock options with BlueDot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, SignalChem, Tarveda, and Turbine; has licensed the HRD assay to Myriad Genetics and DSP patents to Nanostring; and has sponsored research support from AstraZeneca. Dr. Connolly has received research funding from Pfizer; has received research funding to institution for clinical trials from MSD Ireland, Pfizer, Daiichi Sankyo, and AstraZeneca; and has consulted for Seagen and AstraZeneca/Daiichi without renumeration. Dr. Telli reports research support (to her institution) from AbbVie, Arvinas, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, GlaxoSmithKline, Hummingbird Biosciences, Medivation, Merck, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro and Vertex and has received consulting/advisory fees from AbbVie, Aduro Biotech, AstraZeneca, Blueprint Medicines, Celgene, Daiichi Sankyo, Genentech/Roche, Gilead, GlaxoSmithKline, G1 Therapeutics, Guardant, Immunomedics, Lilly, Merck, Natera, Novartis, OncoSec, Pfizer, RefleXion and Sanofi. Dr. Stearns has received research grants (to his institution) from AbbVie, Biocept, Pfizer, Novartis, QUE Oncology, and Puma Biotechnology; is a member of the advisory board for Novartis; is the chair of the Data Safety Monitoring Board for AstraZeneca; and has received nonfinancial support from Foundation Medicine. All other authors have no disclosures to report.

Figures

Fig. 1
Fig. 1
Distribution of GIS by cancer type and BRCA status. (a) The distribution of GIS for BRCA1/2-deficient and BRCA-intact tumors in ovarian cancer, TNBC, and ER + BC. (b) The distribution of GIS for BRCA1/2-deficient tumors fit to a normal distribution for ovarian cancer, TNBC, and ER + BC
Fig. 2
Fig. 2
Distribution of GIS by pCR status for TNBC in (a) the full clinical validation cohort, and (b) the BRCAwt clinical validation cohort. Samples are stratified based on whether pCR was achieved (“pCR” vs. “No pCR”)
Fig. 3
Fig. 3
The probability of pCR in TNBC for a range of GIS from 3-parameter logistic regression models fit for the full clinical validation cohort (N = 211, solid line) and the BRCAwt clinical validation cohort (N = 171, dashed line). The vertical grey dashed lines represent potential thresholds of ≥ 33 and ≥ 42
See this image and copyright information in PMC

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